The misuse and abuse of prescription drugs, particularly pain relievers, has escalated to become the second most common category of substance abuse in the US. While risk of addiction to prescription analgesics when properly used is low, their widespread availability has led to a growing abuse problem, and nonmedical use/abuse of prescription analgesics has doubled. Drugs that decrease NMDA receptor activity have been shown to block sensitization development in pain pathways that underlie progression from acute to chronic pain conditions. Additionally many enhance the analgesic effects of opioids and prevent the development of tolerance and dependence to opioids. Unfortunately, development of NMDA receptor antagonists as medications has been hindered by the production of use-limiting side effects including sedation/motor ataxia and abuse liability as exemplified by the prototypic NMDA antagonist ketamine. The goal of the proposed research is to use preclinical models of abuse-related drug effects and analgesic effects to investigate select NMDA receptor modulators in combination with opioid medications, a clinically relevant pain management approach, to determine if they can provide an improved therapeutic index relative to ketamine. In Aim1 we will investigate whether select NMDA drugs demonstrate diminished rewarding effects relative to ketamine in a self-administration procedure in rhesus monkeys. Additionally, we will assess the reinforcing properties of oxycodone and nalbuphine alone and in combination with the NMDA drugs of interest to determine if they will alter the abuse potential of the opioids. Aim 2 will assess the sedative effects of the NMDA drugs alone and in combination with the opioids using food-reinforced operant responding. In Aim 3, we will assess the therapeutic efficacy of the NMDA drugs alone and in combination with oxycodone or nalbuphine using, a capsaicin-induced model of thermal allodynia in rhesus monkeys. The goal is to identify the compound(s) with improved therapeutic ratios relative to ketamine by comparison of their propensity for production of ketamine- like side effects determined in Aims 1 and 2 to that for production of therapeutic effects in a clinically relevant model of analgesia. In Aim 4 we will investigate the ability of the optimal NMDA drugs to attenuate the development of physical dependence produced by oxycodone and nalbuphine. The individual methodologies are not new, however the use of them in parallel to assess novel NMDA/opioid drug combinations provides a unique approach to evaluating the clinical potential of these combination therapies. The use of nonhuman primates ensures the most phylogenetically appropriate evaluation of the pharmacodynamic and pharmacokinetic interactions of the drugs which enhances the translatability of the results to humans. Identification of safe and effective novel approaches to providing analgesia will significantly improve the medical management of pain and may result in decreased diversion and risk for prescription drug abuse and addiction.